Penicillin binding protein 4: an emerging Staphylococcus aureus therapeutic target

Staphylococcus aureus penicillin-binding protein 4 (PBP4) is a non-essential, low-molecular-weight transpeptidase that contributes to peptidoglycan maintenance under conventional laboratory growth conditions. Several recent studies have suggested that the protein's cellular functions have far-reaching consequences, directly affecting S. aureus success as a human pathogen. Herein, we review recent work implicating PBP4 as a modulator of a noncanonical PBP2A-independent methicillin-resistant S. aureus (MRSA) phenotype that extends to the most recently developed fifth-generation cephalosporins. Furthermore, we review emerging studies indicating that PBP4 is a previously unappreciated virulence factor that governs an essential step in osteomyelitis pathogenesis, namely the invasion of osteocyte lacuna-canalicular networks (OLCNs). Given the protein's involvement in these two disease-related processes, we discuss PBP4's potential as a non-traditional antimicrobial therapeutic target.